Isis Pharmaceuticals announces positive results from ISIS-ANGPTL3Rx Phase 1 study

Isis Pharmaceuticals, Inc. (NASDAQ: ISIS) announced today positive results from a Phase 1 study with ISIS-ANGPTL3_Rx. In this study, healthy volunteers treated with ISIS-ANGPTL3_Rx achieved dose-dependent, statistically significant reductions in angiopoietin-like 3 (ANGPTL3) of up to 93 percent with a mean reduction of up to 84 percent from baseline (p<0.001). In addition, statistically significant reductions from baseline in lipid parameters were observed, including up to 63% with a mean reduction of up to 49% (p<0.01) in triglycerides and up to 46% with a mean reduction of up to 28% (p<0.001) in total cholesterol. ANGPTL3 is a protein that acts as a key regulator of these blood lipids. These data were presented at the 83^rd European Atherosclerosis Society in Glasgow, United Kingdom.

"We are encouraged with the performance of ISIS-ANGPTL3_Rx in healthy volunteers. Based on data from preclinical models of hyperlipidemia, we expect to see even greater lipid reductions in patients with hyperlipidemia than in healthy volunteers," said Richard Geary, senior vice president at Isis Pharmaceuticals. "In fact, in this study we observed that healthy volunteers with higher baseline lipid levels experienced larger lipid reductions than those with lower baseline lipid levels."

"ANGPTL3 is a very interesting target for the management of both plasma triglycerides and cholesterol at the same time. We know from genetic studies of patients who are heterozygous for loss-of-function mutations in their ANGPTL3 gene that they have half-normal levels of plasma ANGPTL3, and correspondingly, lower levels of plasma triglycerides and cholesterol. Patients who are homozygous for such loss-of-function mutations have exceedingly low plasma levels of triglycerides and cholesterol, which are both risk factors for cardiovascular disease. In contrast, humans with different mutations in ANGPTL3 that raise plasma ANGPTL3 levels have increased lipid levels. In addition, pre-clinical studies in animal models demonstrate that raising plasma ANGPTL3 levels increase, and lowering plasma ANGPTL3 levels decrease triglyceride and cholesterol levels," said Joseph L. Witztum, M.D., professor of medicine at the University of California, San Diego. "All of these data strongly support the idea that lowering plasma ANGPTL3 in humans is a potentially important strategy to reduce multiple cardiovascular risk factors."

"ISIS-ANGPTL3_Rx is one of the drugs in our lipid franchise that our wholly owned subsidiary, Akcea Therapeutics, is developing and plans to commercialize. The team at Akcea has already begun to outline the development and commercialization plans for ISIS-ANGPTL3_Rx, together with the other drugs in our lipid franchise, to provide the best opportunity for each drug to succeed and bring the highest possible value to those patients who need these therapies the most," said Lynne Parshall, chief operating officer at Isis.

The Phase 1 study of ISIS-ANGPTL3_Rx was a blinded, placebo-controlled, dose-escalation study in healthy volunteers. The study was designed to assess the safety, tolerability and pharmacokinetics of ISIS-ANGPTL3_Rx. ISIS-ANGPTL3_Rx was evaluated in single and multiple doses ranging from 50 mg per week up to 400 mg per week for the single dose and 100 mg per week up to 400 mg per week for the multiple dose. In this study, ISIS-ANGPTL3_Rx was generally well tolerated.

ISIS-ANGPTL3_Rx is an antisense drug designed to reduce ANGPTL3. ANGPTL3 is produced in the liver and regulates lipid, glucose and energy metabolism. In preclinical studies, antisense inhibition of ANGPTL3 resulted in robust reductions of multiple lipid parameters, including total-cholesterol, and triglycerides. ISIS-ANGPTL3_Rx is part of Isis' lipid franchise and, as such, Akcea Therapeutics, Isis' wholly owned subsidiary, is responsible for developing ISIS-ANGPTL3_Rx.